White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

Abstract

Obesity is a growing global health problem due to its association with chronic low-grade inflammation contributing to metabolic complications. Multiple studies indicate that white adipose tissue (WAT) inflammation can drive the pathogenesis of type 2 diabetes, including altered levels of cells of the innate and adaptive immune system. However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal obese women who either underwent CR for three months followed by a 4 weeks phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and subcutaneous WAT (SAT) (n=21). The T cell receptor repertoire was analyzed by next generation sequencing (n=20) and cytokine levels were determined in SAT (n=22). Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp and then correlated to immune cell subsets. We found that insulin resistance (IR) correlates significantly with a shift towards the memory T cell compartment in SAT. Among various T cell subsets, predominantly CD8+ effector memory T cells were associated with obesity-related IR. Interestingly, T cell receptor analysis revealed a diverse repertoire in SAT arguing against an antigen-driven intra-SAT expansion of effector memory T cells. Surprisingly, neither inflammatory cytokine levels nor leucocyte subpopulations were significantly altered upon CR. Our findings demonstrate the accumulation of effector memory T cells in obese SAT contributing to chronic inflammation. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR induced weight loss.

Immune cell profile and immune‐related gene expression of obese peripheral blood and liver tissue

“…Our findings support the hypothesis, generated from the mice study that enhanced lipid membrane order and T cell activation may contribute to the greater abundance of pro-inflammatory Th1/Th17 memory CD4 + T cells subpopulations observed in human obesity and NAFLD. The presence of these Th1/Th17 memory CD4 + subpopulations appears to be linked to obesity and NAFLD although calorie restriction [18] and gastric banding surgery [45] but have yielded conflicting results as to whether these immune populations normalize after weight loss.…”

“…Studies of the obese immune profile in humans and mouse models have identified consistent key changes in leukocyte population including fewer natural killer (NK) T cells [5][6][7][8], more memory Th1/Th17 CD4 + and CD8 + T cells [9][10][11], monocytes and M1 macrophages [12][13][14][15], and innate Th17 phenotype, MAIT and gamma-delta T cells in peripheral blood, adipose tissue and liver [16][17][18][19][20][21]. The memory Th1/Th17 CD4 + T cells and CD8 + T cells are also responsible for redirecting adipose tissue resident anti-inflammatory M2 macrophages (and recruited monocytes) toward a pro-inflammatory M1 macrophage phenotype [22].…”